This application addresses PAR-12-265, Ancillary Studies to Major Ongoing Clinical Research Studies to Advance Areas of Scientific Interest within the Mission of the NIDDK, through an ancillary study of diverticulitis within two major ongoing epidemiologic studies. Diverticulitis is the third most common gastrointestinal indication for hospitalization in the U.S. as well as a frequent indication for outpatient clinic visits. Litte is known about why a subset of individuals with diverticulosis progress to diverticulitis, and few preventative strategies exist short of segmental colectomy. We have previously identified risk factors for incident diverticulitis in men including low dietary fiber, obesity, physical inactivit, and use of non-steroidal anti- inflammatory drugs using the large, prospective Health Professionals Follow-up Study (HPFS) (n=51,529). Based on this work and the findings of others, recent theories of pathogenesis largely postulate that chronic inflammation and the immune response to intestinal microbiota play important roles in the evolution of diverticulitis. T further address this hypothesis, we propose to examine lifestyle factors and novel biomarkers associated with chronic inflammation and antimicrobial immunity, including pre-diagnostic plasma inflammatory proteins, vitamin D, and cathelicidin, in relation to incident and recurrent diverticulitis. In pursuit of these goals, we will utilize the HPFS as well as a parallel large, prospective cohort of women, the Nurses' Health Study (NHS) (n=121,701) who have been followed with biennial, detailed questionnaires since 1986 and 1976, respectively. We will leverage prospectively collected and validated data on clinical, dietary and lifestyle exposures over extended follow-up prior to the development of diverticulitis as well as available prediagnostic blood samples, offering an unprecedented opportunity to efficiently examine novel risk factors for incident and recurrent diverticulitis, and the role of chronic inflammation in mediating disease pathogenesis. Our findings could have substantial relevance to clinical care and public health as they may: 1) provide opportunities to reduce disease incidence through lifestyle modification; 2) enable the identification of individuals at risk for incident and recurrnt events, therefore facilitating targeted interventions prior to the onset of overt disease; 3) advance our limited understanding of disease etiopathogenesis. Given the prevalence and morbidity of diverticulitis and the lack of predictive and preventative measures, our results could have a profound impact on the management of this disorder.